US5434248AExpiredUtility

Peptidyl derivatives as inhibitors of interleukin-1β converting enzyme

Assignee: MERCK & CO INCPriority: Jun 21, 1991Filed: Jun 2, 1993Granted: Jul 18, 1995

Est. expiryJun 21, 2011(expired)· nominal 20-yr term from priority

Inventors:Kevin T. Chapman Herb G. Bull Malcolm Maccoss Nancy A. Thornberry Jeffrey R. Weidner Adnan M. M. Mjalli

A61P 29/00C07C 233/51A61P 11/00C07C 233/47C07K 5/0202

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Claims

Abstract

Novel peptidyl derivatives of formula I are found to be potent inhibitors of interleukin-1β converting enzyme (ICE). Compounds of formula I may be useful in the treatment of inflammatory or immune-based diseases of the lung and airways; central nervous system and surrounding membranes; the eyes and ears; joints, bones, and connective tissues; cardiovascular system including the pericardium; the gastrointestinal and urogenital systems; the skin and mucosal membranes. Compounds of formula I are also useful in treating the complications of infection (e.g., gram negative shock) and tumors in which IL 1 functions as an autocrine growth factor or as a mediator of cachexia. ##STR1##

Claims

exact text as granted — not AI-modified

What is claimed is: 
     
       1. A compound of formula I ##STR69## wherein Y is: ##STR70## R 1  is C 1-3  alkyl or aryl C 1-6  alkyl wherein aryl is phenyl or naphthyl; R 2  is hydrogen,   AA 1  is selected from the group consisting of (a) a single bond, and   (b) an amino acid of formula AI ##STR71## wherein R 7  is C 1-6  alkyl or aryl C 1-6  alkyl wherein aryl is defined as   (1) phenyl, or   (2) naphthyl, and wherein aryl is optionally mono or di-substituted, the substituents being each independently C 1-6  alkyl, halo, hydroxy, C 1-6  alkyl amino, C 1-6  alkoxy, C 1-6  alkylthio, or C 1-6  alkylcarbonyl;       AA 2  is an amino acid of formula AII ##STR72## AA 3  is an amino acid of formula AIII ##STR73## R 8  and R 9  are each individually (a) hydrogen, C 1-6  alkyl, or   (j) amino-C 1-6  alkyl or N-substituted amino-C 1-6  alkyl wherein the substituent is carbobenzoxy.     
     
     
       2. A compound According to claim 1 wherein: R 1  is methyl or phenyl C 1-6  alkyl or hydroxy-phenyl C 1-6  alkyl;   AA 1  is a single bond or an amino acid of formula AI ##STR74## wherein R 7  is (a) C 1-6  alkyl; (b) substituted phenyl C 1-3  alkyl, wherein the substituent is hydrogen, hydroxy, carboxy, or C 1-4  alkyl;     R 8  is C 1-6  alkyl; and   R 9  is (a) hydrogen,   (b) C 1-6  alkyl,   (c) amino C 1-4  alkyl,   (d) N-carbobenzoxy-amino-(n-butyl).     
     
     
       3. A compound according to claim 2 wherein R 7  is (a) C 1-6  alkyl; or   (b) substituted phenyl C 1-3  alkyl, wherein the substituent is hydrogen or hydroxy.     
     
     
       4. A compound according to claim 3 where R 1  is methyl or phenyl C 1-6  alkyl or hydroxy-phenyl C 1-6  alkyl;   AA 1  is a single bond or tyrosinyl, homotyrosinyl, phenylalaninyl, homophenylalaninyl or tryptophanyl;   AA 2  is ##STR75## wherein R 8  is C 1-4  alkyl; and AA 3  is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       5. A compound according to claim 4 wherein R 1  is phenyl C 1-6  alkyl or hydroxy-phenyl C 1-6  alkyl;   R 2 , R 10  and R 11  are individually hydrogen;   AA1 is a single bond,;   AA2 is ##STR76## wherein R 8  is C 1-4  alkyl; and AA3 is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       6. A compound according to claim 5 wherein R 1  is phenyl ethyl or hydroxy-phenyl ethyl.   
     
     
       7. A compound according to claim to claim 4 wherein R 1  is methyl;   AA 1  is tyrosinyl, homotyrosinyl, phenylalaninyl, homophenylalaninyl or tryptophanyl;   AA2 is ##STR77## wherein R 8  is C 1-4  alkyl; and AA 3  is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       8. A compound according to claim 7 wherein R 1  is methyl;   AA 1  is tyrosinyl;   AA 2  is valinyl, leucinyl or isoleucinyl; and   AA 3  is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       9. A compound according to claim 8 wherein R 1  is methyl;   AA 1  is tyrosinyl;   AA 2  is valinyl;   AA 3  is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       10. A compound selected from the group consisting of: (a)N-(N-Acetyl-tyrosinyl-valinyl-lysinyl)-3-amino-4-oxobutanoic acid;   (b)N-(N-Acetyl-tyrosinyl-valinyl-ε-CBZ-lysinyl)-3-amino-4-oxobutanoic acid; and   (c)N-(N-Acetyl-tyrosinyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid; or a ring chain tautomer or hydrate thereof.     
     
     
       11. A compound selected from the group consisting of: (a) N-(N-Acetyl-phenylalaninyl-valinyl-lysinyl)-3-amino-4-oxobutanoic acid;   (b) N-(N-Acetyl-phenylalaninyl-valinyl-ε-CBZ-lysinyl)-3-amino-4-oxobutanoic acid; and   (c) N-(N-Acetyl-phenylalaninyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid;   (d) N-(3-phenylpropionyl-valinyl-lysinyl)-3-amino-4-oxobutanoic acid;   (e) N-(3-phenylpropionyl-valinyl-ε-CBZ-lysinyl)-3-amino-4-oxobutanoic acid;   (f) N-(3-phenylpropionyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid;   (g) N-(3-(4-hydroxyphenyl)-propionyl-valinyl-lysinyl)-3-amino-4-oxobutanoic acid;   (h) N-(3-(4-hydroxyphenyl)-propionyl-valinyl-ε-CBZ-lysinyl)-3-amino-4-oxobutanoic acid; and   (i) N-(3-(4-hydroxyphenyl)-valinyl-alaninyl)-3-amino-4-oxobutanoic acid;   (n) N-(N-acetyl-tyrosinyl-valinyl-(N,N)-dimethyl-Lisinyl)-3-amino-4-oxo-butanoic acid;   (o) N-(N-phenylpropionyl)valinyl-glycinyl)-3-amino-4-oxo-butanoic acid;   (p) N(N-acetyl-alaninyl)-3-amino-4-oxo-butanoic acid;   (q) N-(N-acetyl-valinyl-alaninyl)-3-amino-4-oxo-butanoic acid;   (r) N-propionyl-3-amino-4-oxo-butanoic acid;   (s) N-(N-acetyl-3-amino-4-oxo-butanoic acid; or   (t) N-(N-Acetyl tyrosinyl-valinyl-histidinyl-3-amino-4-oxo butanac acid.   
     
     
       12. A compound which is N-(N-Acetyl-tyrosinyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid.   
     
     
       13. A compound of formula I ##STR78## wherein Y is: ##STR79## R 1  is C 1-3  alkyl or aryl C 1-6  alkyl wherein aryl is phenyl, naphthyl, thienyl, or benzothienyl; R 2  is R 4     --C--R 6 ,   R 5   wherein R 4  and R 5  are each individually hydrogen;       R 6  is aryl C 1-6  alkyl, wherein the alkyl is substituted with hydrogen, oxo, C 1-3  alkyl, halo or hydroxy wherein aryl is selected from the group consisting of     (1) phenyl,   (2) naphthyl,   (3) pyridyl, and wherein the aryl is optionally mono or di-substituted, the substituents being each independently C 1-3  alkyl, halo, hydroxy, C 1-3  alkyl amino, C 1-3  alkoxy, C 1-3  alkylthio, or C 1-3  alkylcarbonyl;       AA 1  is selected from the group consisting of (a) a single bond, and   (b) an amino acid of formula AI ##STR80## R 7  is C 1-6  alkyl or aryl C 1-6  alkyl wherein aryl is defined as above in this claim, and wherein the aryl is optionally mono or di-substituted, the substituents being each independently C 1-6  alkyl, halo, hydroxy, C 1-6  alkyl amino, C 1-6  alkoxy, C 1-6  alkylthio, or C 1-6  alkylcarbonyl,     AA 2  is an amino acid of formula AII ##STR81## AA 3  is an amino acid of formula AIII ##STR82## R 8  and R 9  are each individually (a) hydrogen, (b) C 1-6  alkyl   (j) amino-C 1-6  alkyl or N-substituted amino-C 1-6  alkyl wherein the substituent is carbobenzoxy, or.     
     
     
       14. A compound according to claim 13 wherein R 6  is phenyl C 1-6  alkyl, wherein the alkyl is substituted with hydrogen, oxo, C 1-3  alkyl, halo or hydroxy, and wherein the phenyl may be mono and di-substituted, the substituents being each independently C 1-3  alkyl, halo, hydroxy, C 1-3  alkyl amino, C 1-3  alkoxy, C 1-3  alkylthio, or C 1-3  alkylcarbonyl;       R 9  is (a) hydrogen,   (b) C 1-6  alkyl,   (c) amino C 1-4  alkyl, or   (d) N-carbobenzoxy-amino-(n-butyl).     
     
     
       15. A compound according to claim 14 wherein R 7  is (a) C 1-6  alkyl; or   (b) substituted phenyl C 1-3  alkyl, wherein the substituent is hydrogen or hydroxy.     
     
     
       16. A compound according to claim 15 wherein R 6  is (a) phenyl methyl,   (b) phenyl ethyl,   (c) phenyl propyl,   (d) phenyl butyl, or   (e) phenyl pentyl;     R 1  is methyl or phenyl C 1-6  alkyl or hydroxy-phenyl C 1-6  alkyl;   AA 1  is a single bond or tyrosinyl, homotyrosinyl, phenylalaninyl, homophenylalaninyl or tryptophanyl;   AA 2  is ##STR83## wherein R8 is C 1-4  alkyl; and AA 3  is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       17. A compound according to claim 16 wherein R 1  is phenyl C 1-6  alkyl or hydroxy-phenyl C 1-6  alkyl;   AA1 is a single bond;   AA2 is ##STR84## wherein R8 is C 1-4  alkyl; and AA3is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       18. A compound according to claim 17 wherein R 1  is methyl, phenyl ethyl or hydroxy-phenyl ethyl.   
     
     
       19. A compound according to claim 18 wherein R 1  is methyl;   AA 1  is tyrosinyl, homotyrosinyl, phenylalaninyl, homophenylalaninyl or tryptophanyl;   AA2 is ##STR85## wherein R 8  is C 1-4  alkyl; and AA 3  is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       20. A compound according to claim 19 wherein R 1  is methyl;   AA 1  is tyrosinyl;   AA 2  is valinyl, leucinyl or isoleucinyl; and   AA 3  is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       21. A compound according to claim 20 wherein R 1  is methyl;   AA 1  is tyrosinyl;   AA 2  is valinyl;   AA 3  is alaninyl, lysinyl or ε-CBZ-lysinyl.   
     
     
       22. A compound selected from the group consisting of: (a) N-(3-Phenylpropionyl-Valinyl-Alaninyl)3-amino-4-oxo-5-phenylpentanoic acid;   (b) N-(3-Phenylpropionyl-Valinyl-Alaninyl)3-amino-4-oxo-6-phenylhexanoic acid;   (c) N-(3-Phenylpropionyl-Valinyl-Alaninyl)3-amino-4-oxo-7-phenylheptanoic acid;   (d) N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-7-phenyl heptanoic acid;   (e) N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-8-phenyl octanoic acid;   (f) N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-9-phenyl nonanoic acid; or   (g) N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-5-hydroxy-4-oxo-7-phenyl heptanoic acid.

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